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Smooth Endoplasmic Reticulum
The Smooth Endoplasmic Reticulum (SER) The Endoplasmic Reticulum (ER) comprises a network of membranes that penetrate much of the cytoplasm, thus, making it one of the largest intracellular compartments. The ER is divided into rough (RER), which is continuous with the nuclear envelope, and smooth (SER); both are connected and continuous (refer to Figure 9), though distinct in terms of structure and function. Depending on the cell type and activities, RER changes to SER and vice versa (Sembulingam and Sembulingam, 2012). The Structure of the Smooth ER In contrast to the RER, Smooth ER lacks ribosomes (figure 9), thus, it is not involved in protein synthesis. The membranes of the SER are highly curved and tubular, forming an interconnecting maze of pipelines permeating the cytoplasm. The high degree of curvature of the SER tubules is maintained by the presence of membrane-bending proteins known as Reticulons, which are largely absent from the flattened RER sheets (Karp, 2013). The Functions of the Smooth ER The functions of the SER are diverse and vary in different cell types (Sembulingam and Sembulingam, 2012): 1) Synthesis of non-protein substances * Synthesis of steroid hormones (in the endocrine cells of the gonad & adrenal cortex) * Synthesis of lipids 2) Catabolism and detoxification * Cytochrome P450 is abundant in the SER in the liver, and it is involved in the detoxification of metabolic waste products, drugs, alcohol, and other organic compounds. 3) Cellular metabolism * The outer membrane of the SER contains many enzymes participate in many metabolic pathways, such as the release of glucose from glycogen in the liver (release of glucose from glucose-6-phosphate from glycogen via glucose-6-phosphotase). 4) Storage of Ca2+ * The SER in muscle cells is known as the sarcoplasmic reticulum and acts by sequestering Ca2+ and releasing them for muscle contraction. Role of smooth ER in detoxification One of the most important functions of the smooth endoplasmic reticulum is the detoxification of drugs and non-drug xenobiotics that include molecules in food, environment or industrial chemicals (Rowland et al. 2013). These detoxification processes occur in the smooth ER in the hepatocytes as the liver is the most metabolically active tissue per unit weight and contains the greatest abundance of smooth ER. The enzymes involved in metabolizing xenobiotics include the cytochrome p450 family (CYPs), UDP- glucuronosyltransferases, glutathione S-transferase (GSTs) and carboxylesterases (Chen et al. 2010; Lavoie and Paiement 2008). CYP450 and UDP- glucuronosyltransferases are considered the most important enzymes and they are responsible for the detoxification of about 90% of drugs in the liver (Rowland et al. 2013). The detoxification pathway involves two phases: phase I or the functionalisation reactions and phase II or the conjugation reactions (as shown in Figure 10) (Rowland et al. 2013; Hodges and Minich 2015). The functionalisation reactions involve the addition of a polar functional group such as a hydroxyl (-OH), carboxyl (-COOH) or amino(–NH2) into the toxic compound by the cytochrome P450 family enzymes (Rowland et al. 2013; Hodges and Minich 2015). These enzymes are monotopic hemoproteins bound to the membrane of the smooth ER and are employed to oxidise, reduce or hydrolyse xenobiotics (Hodges and Minich 2015). After the CYP450 enzymes increase the polarity and water solubility of the xenobiotic, it is now ready for the conjugation reactions in phase II. In phase II, the reactive site of the xenobiotic is conjugated covalently with endogenous hydrophilic compounds (Rowland et al. 2013; Hodges and Minich 2015). These conjugation reactions involve the transfer of hydrophilic groups such as sulfate and amino acids by their corresponding enzymes sulfotransferases and amino acid transferases respectively (Hodges and Minich 2015). All these reactions increase the polarity and hydrophilicity of the metabolites enhancing their excretion in the urine by the kidney or in the bile (as shown in Figure 10) and hence preventing the accumulation of toxic substances (Hodges and Minich 2015). During detoxification, the surface area of the smooth ER doubles and hence the number of cytochrome enzymes and conjugation enzymes increases (Alberts et al. 2002; Sebastián et al. 2006). After detoxification, the excess smooth ER membrane is removed by lysosomes in a process called autophagocytosis that allows the return of smooth ER to its normal state (Alberts et al. 2002; Sebastián et al. 2006).